The study of oral immunity is under-represented at many academic institutions. The goal of this project is to investigate the immunoregulatory role of ?-defensin 3 (BD3) in oropharyngeal candidiasis (OPC) caused by Candida albicans. Interleukin-17 (IL-17) is essential for protection, and BD3 is highly induced by IL-17 during OPC. While BD3 is an antimicrobial peptide with direct anti-Candida activity, it also interacts with chemokine receptor CCR6. The consequences of this interaction during OPC are unknown. Since CCR6+ ??-T cells and nTh17 cells are the main sources of IL-17 during OPC, it is critical to determine how BD3 regulates these and other cells. Knowledge of these cells is limited, and without this study we will not understand the regulation of lymphocytes important in the oral mucosa. Our long-term goal is to understand defensins and innate lympho- cytes in the mucosa during infection, and in pathogenic inflammation associated with oral cancer therapies such as head-neck irradiation. This is a critical relationship to understand since patients receiving radiotherapy are highly susceptible to OPC. The overall objective of this application, which is the next step toward reaching our long-term goal, is to determine how BD3 regulates innate lymphocytes during OPC. Our central hypothesis is that BD3 is essential for protection through the regulation of innate lymphocytes. This hypothesis is based in part on preliminary data produced in the PI's laboratory. The rationale that underlies the proposal is that once it is known how BD3 regulates immune cells in the oral mucosa, therapeutics can be developed that directly kill Candida and modulate the host response effectively. This hypothesis will be tested in the following two specific aims: 1) Determine the contribution of BD3 in immune modulation and protection against OPC; and 2) Identify how BD3 regulates immune cells in the oral mucosa during OPC. In the first aim, BD3KO mice will be subjected to a well-established model of acute OPC to determine susceptibility. Preliminary studies indicate baseline susceptibility of BD3KO mice to OPC, and gene expression studies by RNA-Seq analysis and qPCR will be per- formed in order to determine the inflammatory genes regulated by BD3. The deficiencies in BD3KO saliva will also be determined, an important part of host defense often overlooked by traditional immunologists. In the se- cond aim, flow-cytometric analysis will be employed to determine the cell populations BD3 regulates during infection. Since the cytokine CCL20 can also interact with CCR6, susceptibility and chemotaxis will be investi- gated in CCL20KO compared to BD3KO mice. BD3 protein will be administered to the oral cavities of mice to as- certain the therapeutic potential of BD3 in OPC via regulation of immune cells. The approach of this study is innovative, because it shifts the focus to the regulatory capacity of BD3 in relation to recently described innate lymphocytes. The proposed research is significant, because ultimately with the knowledge of the mediators involved in regulation of the inflammatory response in the oral cavity, better therapeutics can be developed that clear Candida without exacerbating inflammation in immunosuppressed patients suffering from OPC.